DOI: https://doi.org/10.21203/rs.3.rs-2636954/v1
Background: Granulomatous disease is difficult to differential from metastasis cancer, Sarcoidosis is a multisystem granulomatous disease, bone involve is rarely reported.
Case presentation: We report a patient who suspected advanced lung cancer with metastasis mediastinal lymph node and bilateral ilium. However, ilium biopsy showed sarcoidosis involvement. Bronchoscopy and EBUSrevealed adenocarcinoma in right upper lobe lung, with negative mediastinal lymph node. A pathologic analysis of the resected lung tissues led to the correct staging of lung cancer.
Conclusions: coexistent sarcoidosis may mimic metastasis lung cancer, a multidisciplinary team and sequential diagnostic biopsies may avoid unnecessary surgery or insufficient treatments.
Sarcoidosis is a multisystem granulomatous disease, sometimes difficult to differential from metastasis cancer, especially when it coexists with lung cancer. FDG PET/CT are useful in evaluation organ involvements in sarcoidosis or lung cancer. But coexistent sarcoidosis in lung cancer may lead to misdiagnose or incorrect staging. We present a case of bone involvement with sarcoidosis in early non-small cell lung cancer, and no similar case has been reported.
A 57-year-old female patient went to the clinic in in August 2018, presented with a mild cough that had persisted for 4 months. She had a history of surgery for thyroid cancer in 2010, and denied any history of pulmonary disease. A chest CT scan performed immediately revealed a single cavitary lesion in the right upper lung, diffuse small perilymphatic nodules in both lungs, and enlarged hilar and mediastinal lymph nodes. In October 2018, FDG PET/CT revealed mild 18F-fluorodeoxyglucose (FDG) uptake in the right upper lesions and multiple bilateral lung nodules, and intense FDG uptake in the mediastinal and bilateral iliac lymph nodes (Fig. 1). MRI of the ilium revealed multiple bilateral osteolytic lesions that appeared to be bone metastases (Fig. 2). Lung cancer with multiple metastasis was suspected. But biopsy of the ilium revealed epithelioid granulomas with small necrotic areas (Fig. 3a). Periodic acid–Schiff (PAS), acid-fast, and Grocott’s Methenamine Silver (GMS) stains yielded negative results. The diagnose of sarcoidosis was considered.
Bronchoscopy revealed multiple mucosal nodules in the right middle bronchus(Fig. 4a and b). Radial endobronchial ultrasound with a guide sheath and endobronchial ultrasound needle aspiration (EBUS-TBNA) was performed, and the pathological findings indicated an adenocarcinoma in the right upper lung, non-necrotizing granulomas in the right middle bronchial mucosa, and no malignant cells in the station 4R and 7 lymph nodes. An acid-fast bacilli stain and tuberculosis culture of bronchoalveolar lavage fluid yielded negative results.
The patient underwent a resection of the right upper lung lobe and part of the right middle lobe. A pathologic analysis of the surgical specimen revealed adenocarcinoma with surrounding granulomas in the right upper lung lobe (Fig. 3b) and granulomatous nodules in the right middle lung lobe. The postoperative pathological stage was pT1N0M0, with coexistent sarcoidosis. She refused to take any corticosteroids for treatment of sarcoidosis after surgery. The patient did not exhibit any sign of recurrent lung cancer until last follow up in January 2020.
In our case, the patient was misdiagnosed with advanced lung cancer according to the PET/CT, whereas the bone biopsy and EBUS results suggested an early-stage malignancy, sarcoidosis involved ilium, which was finally confirmed by a pathologic analysis of the surgically resected sample. Sarcoidosis is a multiorgan disease that manifests as non-caseating granulomas of unknown etiology. Sarcoidosis may involve all organs to different degrees. However, bone involvement is rare, with an incidence of 3.4% [1], and such lesions are easily misdiagnosed as bone metastases. A bone biopsy is important for an accurate diagnosis, as it is difficult to differentiate bone metastases and sarcoidosis on PET/CT and MRI [2]. Tumor and nodule reactions may coexist in lymph nodes of patients with non-small cell lung cancer, but they are rare [3]. Of the 1029 cases of sarcoidosis, 50 patients were initially diagnosed with malignant tumors after sarcoidosis, 36 cases of malignant tumors were not associated with sarcoidosis, the length of time between the diagnosis of sarcoidosis and malignant tumors (> 1 year), the involvement of organ system (different from nodules and cancer), and the treatment of no potential carcinogenic sarcoidosis. And 7 cases of subsequent cancer diagnosis may be related to sarcoidosis treatment. The diagnosis of sarcoidosis in 7 cases resulted in a one-month to two-year delay in the final cancer diagnosis, including Hodgkin's lymphoma, mucosa-associated lymphoid tissue tumor, lymphomatoid granuloma, head and neck squamous cell carcinoma, seminoma and skin T-cell lymphoma [4].
According to previous research, sarcoidosis patients have a significantly increased risk of malignant tumors[4–6]. Patients diagnosed with sarcoidosis were later discovered to have malignant tumors, either because the diagnosis of sarcoidosis was based on the granulomatous response to malignant tumors, or because the treatment of sarcoidosis was related to malignant tumors, or because sarcoidosis patients were essentially at risk for malignant tumors. Therefore, patients who have been identified with sarcoidosis need to have a screening for malignant tumors as part of both their physical examination and their follow-up care[4–6].The link between cancer and sarcoidosis is not well understood. Patients with known sarcoidosis may have subsequent or concomitant malignancy. Although the underlying mechanism is unclear, this event may be related to a chronic inflammatory response[7]. Some studies found that cancer patients with granuloma had a higher chance of survival and a lower incidence of stage 4 disease (OR = 0.195, 95% CI 0.073–0.521, p = 0.001). Granuloma can be employed as a prognostic biomarker, and the 2-, 4-, 6-, and 10-year survival rates following cancer diagnosis are greatly improved. Although the actual mechanism of granuloma formation is unknown, it is possible that they are immunological reactions to tumor components. If proven, they could be employed as immunotherapy treatment biomarkers[8]. Active sarcoidosis is distinguished by increased local expression of T helper 1 (Th1) and Th17 chemokines and cytokines such as IFN-, TNF-, IL-17A, and IL-22. In Th17 cells, lower levels of cytotoxic T lymphocyte antigen 4 (CTLA-4) and higher levels of PD-1 (programmed death 1) restrict the inflammatory response. The immune response of sarcoidosis and tumor patients increases sarcoidosis-related inflammation by maintaining low levels of anti-inflammatory CTLA-4 expression while limiting tumor-specific T cell activation, which is characterized by elevated PD-1 expression. Allows malignancies to evade the immune system and spread[9, 10].
Our results suggest that a multidisciplinary team and sequential diagnostic biopsies is necessary for achieving a correct diagnosis and avoiding unnecessary surgery or insufficient treatments. Sarcoidosis is most commonly found in solid or blood cancers before, during, or after the development of the disease. In many circumstances, diagnosis might be difficult and necessitates careful diagnostic testing.
NSCLC: Non-small-cell Lung Cancer.
Acknowledgements
We thank all the staff at the Department of Thoracic Surgery for their help.
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Written informed consent for publication of case report was obtained from the patient.
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Competing interests
The authors declare that they have no competing interests.
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The authors declare that there was no funding regarding this manuscript.
Authors' contributions
XZ and YC - diagnostic work-up, follow-up, data collection, write the manuscript. WW – pathologic diagnose. All authors read and approved the final manuscript.